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Pharmacokinetics of Dapaconazole, A Novel Antifungal Agent, in Beagle Dogs and Inhibition of Cytochrome P450 Family 51

[ Vol. 16 , Issue. 1 ]

Author(s):

Juliana S. Palo*, Noedi L. de Freitas, Samuel G.N.e Silva, Julio A. Rojas-Moscoso, Tiago Zaminelli, Caroline H. Lescano, Gustavo D. Mendes and Gilberto De Nucci   Pages 15 - 21 ( 7 )

Abstract:


Objectives: Pharmacokinetics of dapaconazole and inhibition of cytochrome P450 family 51.

Methods: Pharmacokinetics of dapaconazole, a novel imidazolic antifungal compound, was studied in male beagle dogs following intravenous (1, 2 and 20 mg/kg) and oral (20 mg/kg) administration.

Results: Oral bioavailability was calculated to be 97.3%. The elimination half-life (t½) after intravenous administration was 2.1-2.5 h, the total body clearance was 2.5-4.2 L/h/kg and the apparent volume of distribution was 9.0-14.4 L/kg. Dapaconazole caused concentration-dependent inhibition of cytochrome P450 family 51 (CYP51) activity with an IC50 of 1.4 ± 0.3 μM (mean ± SEM, n=3), compared to that of ketoconazole (IC50 = 1.2 ± 0.6 μM, n=3).

Conclusion: Results indicate that dapaconazole could be a potentially useful drug for systemic administration.

Keywords:

Azole antifungals, mass spectrometry, bioavailability, ketoconazole, tandem mass spectrometry, 14-α-demethylase.

Affiliation:

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Faculty of Medicine, Camilo Castelo Branco University, São Paulo, SP, Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP

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